Phenotypic screening using DNA-encoded libraries

使用 DNA 编码文库进行表型筛选

• 批准号: 10238888
• 负责人: Thomas J. Kodadek
• 金额: $ 59.51万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-04-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238888
• 关键词: Affect; Agonist; Animals; Biochemical; Biological; Biological Assay; Biological Process; Biology; Categories; Cells; Charge; Cleaved cell; Complex; DNA; Development; Engineering; Environment; Exhibits; Fishes; Fluorescence; Generations; Goals; Incubated; Infrastructure; Laboratories; Libraries; Ligands; Link; Membrane; Molecular Target; Permeability; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Process; Proteins; RNA; Reporter Genes; Reporting; Research Personnel; Rest; Signal Transduction; Specialized Center; Structure; Surface; System; Technology; Tentagel resin; Whole Organism; Work; base; cellular engineering; chemotherapy; flasks; fluorescence activated cell sorter device; high throughput screening; innovation; interest; novel; novel strategies; screening; small molecule

Project Summary This project will focus on the development of a powerful new approach for the discovery of bioactive small molecules via cell-based phenotypic screening. DNA-encoded one bead one compound libraries built on small beads will be complexed with cells and suspended in solution. A photolabile linker will be cleaved, exposing the cells briefly to a high local concentration of the compound on the bead to which they are attached. The cells will be engineered to report a phenotype of interest through the increase of a fluorescent signal. Beads carrying positive cells will be isolated by FACS and the encoding tags sequenced, revealing the structures of the hits. Since we will use libraries of molecules capable of linking to targets covalently, the identification of the target will be simplified greatly. This system will be used to discover novel new chemotherapy agents.

项目概要 该项目将重点开发一种强大的新方法来发现生物活性小分子 通过基于细胞的表型筛选分子。基于小型 DNA 编码的一珠一化合物库 珠子将与细胞复合并悬浮在溶液中。不耐光的连接子将被切割，暴露 细胞短暂地接触到它们所附着的珠子上局部高浓度的化合物。细胞 将被设计为通过增加荧光信号来报告感兴趣的表型。携带珠子 阳性细胞将通过 FACS 分离，并对编码标签进行测序，揭示命中的结构。 由于我们将使用能够共价连接目标的分子库，因此目标的识别 将大大简化。该系统将用于发现新型化疗药物。